5-deutero-2,4-thiazolidinedione derivatives and compositions comprising and methods of using the same

Abstract

The invention provides 5-deuterium-enriched 2,4-thiazolidinediones (e.g., 5-[4-[2-(5-ethyl-2-pyridyl)-2-oxoethoxy]benzyl]-5-deutero-thiazolidine-2,4-dione), deuterated derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salt forms thereof, and methods of treatment using the same.

The invention claimed is: 
     
       1. A deuterium-enriched compound represented by formula V or a stereoisomer or pharmaceutically acceptable salt form thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 10  is H or D; 
         Z is H or D, provided that the abundance of deuterium in Z is at least 30%; 
         R A  is selected from: H, halo, C 1-4  alkyl optionally substituted with 1 halo, and C 1-4  alkoxy optionally substituted with 1 halo; and 
         R 11  is selected from: OH and OD. 
       
     
     
       2. The deuterium-enriched compound of  claim 1 , wherein the compound is a compound of formula Va or Vb or a pharmaceutically acceptable salt form thereof: 
       
         
           
           
               
               
           
         
         wherein the compound has an enantiomeric excess, with respect to the C—Z carbon, of at least 5%. 
       
     
     
       3. The deuterium-enriched compound of  claim 1 , wherein the compound is a compound of formula Vc, Vd, Ve, or Vf or a pharmaceutically acceptable salt form thereof: 
       
         
           
           
               
               
           
         
         wherein the compound has a stereomeric purity of at least 5%. 
       
     
     
       4. The deuterium-enriched compound of  claim 1 , wherein the abundance of deuterium in Z is selected from: (f) at least 90%, (g) at least 95%, (h) at least 97%, and (i) about 100%. 
     
     
       5. The deuterium-enriched compound of  claim 2 , wherein the enantiomeric excess, with respect to the C—Z carbon, is selected from: (h) at least 80%, (i) at least 90%, (j) at least 95%, (k) at least 97%, (l) at least 98%, and (m) at least 99%. 
     
     
       6. The deuterium-enriched compound of  claim 2 , wherein the enantiomeric excess, with respect to the C—Z carbon, is at least 90%. 
     
     
       7. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of  claim 1 . 
     
     
       8. A method of treating a metabolic inflammation-mediated disease selected from the group consisting of Type I diabetes, Type II diabetes, insulin resistance, and inadequate glucose tolerance, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of  claim 1  to treat the disease. 
     
     
       9. A method of treating nonalcoholic steatohepatitis (NASH), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of  claim 1 .